European Commission approves label extension for Xtandi (enzalutamide)for the treatment of adult men with high-risk biochemical recurrent (BCR) non-metastatic hormone-sensitive prostate cancer

The extended approval for Xtandi is based on results from the Phase III EMBARK trial in 1,068 men with high-risk BCR nmHSPC, in whom levels of prostate-specific antigen (PSA), the biomarker which can be indicative of prostate cancer activity, doubled in nine months or less. The study showed patients treated with Xtandi in combination with leuprolide had a 57.6% lower chance of their cancer spreading or dying compared to those treated with leuprolide alone. Participants who were treated with Xtandi alone had a 36.9% reduction in risk.

The European Association of Urology (EAU) revised their treatment guidelines in April 2024, recommending enzalutamide for men with high-risk BCR nmHSPC with or without ADT, after radiation therapy or surgery. Up until now, there has been no consensus on the standard of care for men in this setting.

Dr. Antonio Alcaraz, Chairman of the Department of Urology at the University Hospital Clinic of Barcelona: "When non-metastatic hormone-sensitive prostate cancer recurs and is allowed to evolve, it could potentially lead to metastasis. Facing a particularly high risk and poorer outcomes in this stage of prostate cancer are men with a rapidly rising PSA, where PSA levels double within 9 months. It is critical to manage the cancer carefully then, and I urge clinicians not to delay treatment in this setting. With this expanded approval for enzalutamide, clinicians now have an important new option to treat men with non-metastatic hormone-sensitive prostate cancer at high risk of metastasizing, which could become a new standard of care."

Ernst-Günther Carl, Chairman, Europa Uomo: "There is a desperate need for additional effective treatment options for those living with advanced prostate cancer. Many men with hormone-sensitive prostate cancer undergo arduous surgery and rounds of radiotherapy, which can be a successful way to keep their cancer at bay. It is devastating then, when up to four in ten of those will go on to develop a recurrence that puts them at significantly greater risk of their cancer spreading and early death. The patient community welcomes any ongoing therapeutic research advances that may benefit those living with prostate cancer in progress."

Xtandi was approved by the FDA for the treatment of patients with non-metastatic castration-sensitive prostate cancer (nmCSPC; also known as nmHSPC) with BCR at high risk for metastasis in November 2023.

About EMBARK The Astellas- and Pfizer-led Phase I II, randomized, double-blind, placebo-controlled, multi-national trial enrolled 1,068 patients with nonmetastatic hormone- (or castration-) sensitive prostate cancer (nmHSPC or nmCSPC) with high-risk BCR at sites in the U.S., Canada, Europe, South America, and the Asia-Pacific region. Patients who were considered to experience high-risk BCR had a prostate-specific antigen doubling time (PSA-DT) less than 9 months; serum testosterone greater than 150 ng/dL (5.2 nmol/L); and screening PSA by the central laboratory greater than 1 ng/mL if they had a radical prostatectomy (with or without radiotherapy) as primary treatment for prostate cancer, or at least 2 ng/mL above the nadir if they had radiotherapy only as primary treatment for prostate cancer. Patients in the EMBARK trial were randomized to receive enzalutamide 160 mg daily plus leuprolide (n=355), enzalutamide 160 mg as a single agent (n=355), or placebo plus leuprolide (n=358). Leuprolide 22.5 mg was administered every 12 weeks. EMBARK met its primary endpoint of metastasis-free survival (MFS) for the Xtandi plus leuprolide arm, demonstrating a statistically significant reduction in the risk of metastasis or death over placebo plus leuprolide. MFS is defined as the duration of time in months between randomization and the earliest objective evidence of radiographic progression by central imaging or death due to any cause, whichever occurred first. The study also met a key secondary endpoint, by demonstrating that patients treated with XTANDI (single agent) had a statistically significant reduction in the risk of metastasis or death versus placebo plus leuprolide, meeting its MFS endpoint.

In EMBARK, Grade 3 or higher adverse events (AEs) were reported in 46% of Xtandi plus leuprolide patients, 50% of patients treated with Xtandi (single agent), and 43% of patients receiving placebo plus leuprolide. Permanent discontinuation due to AEs as the primary reason was reported in 21% of Xtandi plus leuprolide patients, 18% in Xtandi (single agent) patients, and 10% in placebo plus leuprolide patients.

About High Risk Biochemical Recurrent Non-Metastatic Hormone Sensitive Prostate Cancer: In non-metastatic hormone (or castration-) sensitive prostate cancer (nmHSPC or nmCSPC), no evidence of the cancer spreading to distant parts of the body (metastases) is detectable with conventional radiological methods (CT/MRI), and the cancer still responds to medical or surgical treatment designed to lower testosterone levels. Of men who have undergone definitive prostate cancer treatment, including radical prostatectomy, radiotherapy, or both, an estimated 20-40% will experience a BCR within 10 years. About 9 out of 10 men with high-risk BCR will develop metastatic disease, and 1 in 3 will die as a result of their metastatic prostate cancer. The EMBARK trial focused on men with high-risk BCR. Per the EMBARK protocol, patients with nmHSPC and high-risk BCR are those initially treated by radical prostatectomy or radiotherapy, or both, with a PSA-DT 9 months. High-risk BCR patients with a PSA-DT of less than 9 months have a higher risk of metastases and death.